Liver fibrosis arises from the excessive accumulation of extracellular matrix proteins including collagen that occurs in most types of chronic liver diseases. Non-alcoholic fatty liver disease (NAFLD) is a medical condition that is characterized by the buildup of fat (called fatty infiltration) in the liver. Up to 85% of patients with NAFLD have diabetes or impaired glucose tolerance. Nonalcoholic steatohepatitis (NASH) is the most severe form of NAFLD in which there is fatty infiltration along with liver inflammation (steatohepatitis). NASH affects 2 to 5 percent of Americans.
Both NASH and NAFLD are becoming more common, possibly because of the increased rate of obesity. Obesity also contributes to diabetes and high blood cholesterol, which can further complicate the health of someone with NASH. Better treatments for liver fibrosis which may be associated with non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), emerging cirrhosis, non-cirrhotic hepatic fibrosis, type 2 diabetes mellitus (T2DM) or metabolic syndrome (MS) are currently needed.
CCR2 antagonists have been described in U.S. Pat. Nos. 8,519,135, 7,622,583, 7,884,110, and 8,093,247 and U.S. Patent Publication 2006/0173019.